Process for preparation of samples for analysis

ABSTRACT

An automated sample preparation system for chemical assay of samples of materials. The sample preparation system includes a sample preparation chamber which includes a removable cup for taking solid or very viscous samples to the sample preparation system. The cup may be attached in sealing relationship to a cap through which extends various utilities such as a mixer/grinder to grind solid samples and mix non-homogeneous samples, a fill pipe to pump in liquid samples, an effluent pipe in the sump of the cup to allow pumping of samples and solvents and a nozzle to allow liquids to be sprayed against the walls. A sample metering valve associated with the sample preparation chamber allows a known volume of sample to be isolated so that solvent may be pumped in to dilute the sample to a user defined concentration. A reversible pump is coupled by a pair of manifolds which are themselves coupled by solenoid operated valves to various sources of solvents, pressurized gas, vacuum, water, the sample preparation chamber and the assay system. A control system coordinates the operation of all remotely controllable units in the system to allow the user to customize various sample preparation processes.

This application is a division of application Ser. No. 942,353, filed12/16/86.

BACKGROUND OF THE INVENTION

The invention pertains to the field of sample preparation systems forautomated chemical analysis. More, particularly, the invention relatesto the field of systems for processing liquid, solid or slurry samplesfor analysis by liquid chromatography systems.

In many chemical processing plants or laboratories, there is a need forchemical assays for determining the components and/or proportions of thechemical material being dealt with or made. Often this is done using aliquid chromatography system (hereafter liquid chromatography will bereferred to as LC). To be suitable for analysis by liquidchromatography, the sample or sample solution must be homogenous,dissolved in an appropriate solvent, and of known concentration (ifdiluted).

The types of samples which must be dealt with are often quite varied,and often the manner of isolating an aliquot of sample to analyze isquite varied. For example, the sample preparation system may be calledupon to prepare samples that are non-homogeneous, two phase,liquid/liquid or liquid/solid samples or slurries with entrained gasbubbles or foam. Further, the samples may be solid in either granulated,powder or tablet form. Some samples may be quite viscous while othersare quite thin. Some samples may need to be taken from vats or tankswhere they are stored or prepared while other samples may need to betaken from a process stream. Some samples are susceptible to pumpinginto the sample preparation system while other samples are solid or tooviscous to pump and must be physically picked up by an operator of thesample preparation system.

Often it is necessary to dilute samples with solvents before pumpingthem through an LC column. Very precise control of the sampleconcentration is necessary in this case. To obtain this precise control,there must be some way to isolate a known volume of sample from the restof the sample and to release it into a known quantity of diluent.

Prior art sample preparation systems have, to date, not been capable ofhandling all the above noted situations gracefully. Generally, prior artsample preparation systems are capable of handling only one type ofsample, and major modifications or use of an entirely different systemis needed to handle a different type of sample.

Thus there has arisen a need for a single sample preparation systemwhich can easily and conveniently handle all the different types ofsamples which may be necessary to analyze.

SUMMARY OF THE INVENTION

In accordance with the teachings of the invention, there is provided asample preparation system which can handle samples of the liquid, solidor slurry type. The system includes a sample preparation chamber havinga removable cup which may be taken to the location of solid or extremelyviscous samples and a measured amount of sample may be placed therein.The cup has a sloped bottom with a sump point or region which is lowerthan all other regions of the bottom. The cup attaches in any known,sealing manner to a cap. Through the cap are a fill/empty pipe throughwhich the cup may be filled by pumping in liquid sample, solvent ordiluent. The fill/empty pipe outlet is at or near the lowest point ofthe bottom, so the cup may also be emptied through this fill/empty pipe.

A solenoid operated or pneumatically operated sample metering valve isalso provided with an inlet in the cup to allow a known volume of sampleto be isolated from the rest of the sample. A nozzle is provided alsowhereby the walls of the cup may be washed down by pumping of solventinto the cup through the nozzle which deflects the solvent against thewalls of the cup. After all excess sample and solvent has been pumpedout of the cup, the isolated aliquot of sample may be released back intothe cup, and a known volume of diluent may be pumped in to dilute thesample to the desired concentration.

For non-homogeneous samples or solid samples which must be ground intosmaller particles prior to being dissolved, a mixer/grinder is provided.This device includes a drive apparatus for imparting rotational motionto a shaft which is connected to a propeller/grinder which is located inthe cup.

For some applications, other mixers such as ultrasonic mixers similar tothe one distributed by Sonics and Materials in Danbury, Connecticut, ora high speed homogenizer similar to the one distributed by Brinkman inWestbury, N.Y. may be substituted. In some applications, use of thesealternate mixers would be preferred.

An electrically or pneumatically driven reversible pump mechanism whichis capable of accurate, repeatable delivery of user specified volumes ofliquid provides the facility to move liquids into and out of the cup andto pump them to the injection port of a system. The pump is coupledthrough two solenoid operated valves to two manifolds. The inlet andoutlet manifolds are merely a collection of valves configured toaccomplish a desired task or series of tasks. These tasks may includedilution, extraction, sampling, solid phase extraction, low pressurechromatography and others, and may be connected to a variety of otherequipment. These include the LC or other analyzer, the effluent (waste)line, several sources of different solvents, a source of pressure, asource of subatmospheric pressure, a water supply, an electrically orpneumatically driven six way valve for bringing in liquid or slurrysample from a vat or storage tank, the nozzle in the cup and a samplevalve in a process stream. The process stream sample valve is alsocoupled to the effluent line through a two way solenoid operated orpneumatically driven valve.

A control circuit or system is coupled to the solenoid operated valves,the pump, the six way valve, the two way valve, the sample meteringvalve and the mixer/grinder drive mechanism. The control circuitimplements a user interface by which the user may specify the operationsto be performed by the system, and the parameters for the process to beperformed. The control system then issues the proper control signals tothe various elements in the system in the proper sequence to cause thedesired sample preparation process to occur.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram of the system of the invention.

FIG. 2 is a cross sectional view of one type of sample metering valve ofthe invention with its piston extended.

FIG. 3 is a cross sectional view of the sample metering valve of FIG. 2with the piston retracted so as to isolate the sample.

FIG. 4 is a cross sectional view of another type of sample meteringvalve for handling slurries or other samples with gas bubbles thereinwhich must be compressed.

FIGS. 5 through 8 are views of the sample metering valve of FIG. 4 invarious states of its operation of drawing sample liquid, compressingany entrained gas, and determining the final, compressed volume.

FIG. 9 is a diagram of another type of sample metering valve suitablefor sampling slurries.

FIG. 10 is a symbolic diagram of a 6 way valve in a first state whichmay be used to replace the sample metering valve for certain types ofsamples.

FIG. 11 is a symbolic diagram of the 6 way valve of FIG. 10 in a secondstate.

FIG. 12 is a diagram of an alternative embodiment of the basic inventionwhere the collection of valves constituting the two manifolds in FIG. 1are replaced in part by multiport rotary valves.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Referring to FIG. 1 there is shown a diagram of the sample preparationsystem of the invention. The system includes a sample preparationchamber 10 the details of which are given in U.S. patent application"Sample Preparation Chamber With Mixer/Grinder and Sample AliquotIsolation", Ser. No. 942,198, filed Dec. 16, 1986 which is herebyincorporated by reference. For completeness here, a short summary of itsstructure and operation will be given.

The sample preparation chamber is capable of being used to prepare manydifferent types of samples for chemical assay, especially by liquidchromatography. The sample preparation chamber is comprised of a slopedbottom cup 12 which is lightweight, transparent and disposable forholding the sample liquid or solid. The cup threads or otherwiseattaches to a cap 14 which serves to keep liquids in by a liquid seal 16between the cup flange and the mating cap flange. The detachability ofthe cup allows the cup to be removed and taken to the location of thesample so that a measured amount of sample may be placed therein forsolid samples which cannot be pumped as symbolized by the weighingmachine 18. Several elements pass through the cap. These elementsinclude a fill/drain pipe 20 which extends to the lowest point 22 in thesloped bottom 24 of the cup and has a diameter which is large enough topump viscous liquids through without excessive pressure being required.A second fill pipe 26 also passes through the cap, but does not extendto the bottom of the cup. In the preferred embodiment, the fill pipe 26is adjustable such that the height of the bottom of the fill pipe fromthe bottom of the cup 12 may be either manually adjusted or adjusted byany known mechanism acting under the control of the control system 98.This fill pipe may have a smaller inside diameter than the fill/emptypipe 20, and may be used to pump liquid sample, solvents or diluent intothe cup, especially less viscous liquid samples.

There is also a nozzle 28 which extends through the cap 14. This nozzleis used to wash down the side walls of the cup 12. The nozzle 28 is apropeller like structure in line with the outlet of a pipe 29. To usethis feature, the user pumps solvent or some other liquid through thepipe 29 connected to the nozzle. The fluid flow causes the propeller ornozzle element to spin. This deflects fluid laterally out toward theside walls of the cup 12 thereby washing down the walls.

The sample container also includes a mixer/grinder mechanism 30A. Thismechanism includes a motor 30 driving a shaft 32 which passes throughthe cap 14. The shaft 32 is coupled to a propeller 34 or other stirringstructure which may or may not be suitable for grinding solid samples.The user may change the structure of the mixer/grinder propeller 34 tobest suit the types of samples the user customarily prepares for assay.For example, high speed homogenizers or ultrasonic probes may besubstituted.

A sample metering valve 36 is also provided for allowing the user toisolate a known volume of sample from the rest of the material in thecup. In the particular embodiment shown in FIG. 1, the sample volume isisolated in a portion of the sample metering valve. This known volumemay then be released back into the cup 12 after the rest of the samplehas been pumped to waste through an effluent line 20. The samplemetering valve 36 and the mixer/grinder 30A may both be driven either byan electrical motor or a pneumatic drive mechanism. Those skilled in theart will appreciate an adequate drive mechanism for the mixer/grinder30A. The details of the sample metering valve are given in U.S. patentapplication "Sample Metering Valve For a Sample Preparation System",filed Dec. 16, 1986, Ser. No. 942,201 which is hereby incorporated byreference. For completeness here, a short summary of the different typesof sample valves will be given.

The sample metering valve is shown in the extended position in FIG. 2.This valve is a device which can repeatedly and accurately isolate aknown volume of sample from a larger volume of sample. The samplemetering valve used in the invention includes an open end cylinder 13 inwhich there is positioned a piston 11 having a T shaped sealing end plug15 having a tip 23. The piston 11 slides back and forth in the cylinder13 within the confines of retaining rings 17, 27 and material 29Abetween an extended position (indicated by the numeral 24), shown inFIG. 2 and a retracted position shown in FIG. 3. The T shaped sealingend plug 15 is sized so as to form a sealing plug in the open end 19 ofthe cylinder. A cylindrical recess 21 is formed in the piston 11 and isplaced on the piston 11 such that the recess 21 is exposed to thesurrounding medium when the piston 11 is in the extended position. Thiscauses the recess 21 to fill up with the material of the surroundingmedium when the piston 11 is extended. When the piston 11 is retracted,the material in the recess 21 is isolated.

No O ring seals are used on the piston 11 in the valve of the invention.Instead, a soft material 29A is sandwiched at both ends 7 and 33 betweentwo harder retaining rings 17 and 27. A spring 31 is disposed inside thecylinder concentrically around the piston 11. This spring 31 contactsthe retaining ring 27 of relatively harder material at the end farthestfrom the sealing plug 15 on the piston 11. The purpose of the spring 31is to apply a bias force along the negative y axis to the relativelyharder ring to exert pressure on the softer material 29A, which in thepreferred embodiment is a sealing cylinder, to cause it to expandagainst the side wall of the piston 11 thereby forming a better seal.Because there are no gaps between the relatively harder sealing rings 17and 27 and the relatively softer sealing cylinder 29A and because theintersections between the rings 17 and 27 are not exposed to thesurrounding medium when the piston 11 is extended, no dead volume isavailable to fill with unknown volumes of sample.

Typically, the piston 11 is driven either by a pneumatic system or bystepper motors (not shown).

Another embodiment of a metering sample valve is a syringe type valveshown in FIGS. 4 through 8. This valve is especially useful in dealingwith slurries with entrained gas bubbles or foam. These bubbles of gastake up volume in an isolated sample which can lead to inaccuracy inpredicting the actual volume of liquid which has been isolated in ametering valve. The syringe tube sample metering valve 11 utilizes acylinder 37 with a piston 41 therein and a separately movable end plugor valve 39. The end plug 39 is moved to an open position so that thesurrounding medium 51 may enter the cylinder 37 through an opening 35.During filling of the valve, the piston 41 is drawn by a piston drivemechanism 47 to the piston's retracted position to create more volumeinside the cylinder 37 thereby lowering the pressure inside the cylinderand causing the it to fill with sample. After the cylinder sample volumeis filled, the valve 39 is closed and piston 41 is separately moved downtoward the valve 39 thereby compressing any gas bubbles entrained in orotherwise trapped in the sample volume of the cylinder 37. During thisdownward movement of the piston 41, the amount of movement, i.e., thedistance the piston 41 moves toward the valve during the compressionstroke, is monitored by a sensor (not shown but part of the piston drivemechanism 47). When the piston has moved far enough to satisfy a userdefined criteria, such as spill from the valve 39 caused by thecompression pressure slightly exceeding the force with which the valve39 is held closed by the valve drive mechanism 43, the total movement ofthe piston 41 is determined. This done by direct measurement,interpolation of sensor output data from the sensor or by reading themotor step number in the case of a stepper motor drive 47 for the piston41. The total volume of liquid in the syringe valve 11 is calculated bysubtracting the volume displaced by the movement of the piston towardthe valve 39 during the compression stroke from the total originalvolume of sample in the cylinder before the beginning of movement of thepiston during the compression stroke.

The sample may then be released by causing the valve 39 to unseal thecylinder and either letting the sample flow out of the cylinder 37 or bypushing it out by further movement of the piston 41. With liquidsamples, especially very viscous samples, the syringe type embodimenthas the added advantage that the process of filling the cylinder samplevolume with sample may be speeded up by using the piston to draw up thesample into the cylinder by moving it away from the sealing plug from aposition adjacent to the sealing plug at the time the plug is opened.

The preferred embodiment of the sample metering valve for use in slurryand other sample situations where the volume consumed by gas bubblesexists is comprised of three, three way valves coupled to a samplemetering pump and a source of pressurization (gas in this example) asshown in FIG. 9. A first three way valve A (basically a Y valve) has itscommon port 3 coupled to a fill pipe 20 in a sample chamber 54. Thenumber 1 port of valve A is coupled to the number 1 port of anotherthree way valve B. This connection forms a sample chamber 64 between thevalve mechanisms of the first and second valves, A and B respectively.The number 2 ports of the two valves A and B are coupled together toform a bypass loop 74. The common port 3 of the second valve B iscoupled to the common port 3 of a third three way valve C which has oneof its ports, port 2, coupled to the sample pump 70 and the other port,port 1, coupled to the source of pressurized gas at source pipe 76.

The valves A, B and C are operated to couple the sampling pump 70 tofill tube 20 in the chamber. The sample pump is driven so as to sucksample up through the fill tube 20 into the first valve A and outthrough the sample chamber 64 until enough sample is drawn to completelyfill the sample chamber 64 and excess sample is drawn through the valveB into pipe 66 which excess sample is sufficient in volume to compensatefor the effects of compression. The first valve A number 1 port is thenclosed by turning its valve plate 50 to isolate the sample in the samplechamber 64 and the third valve C is operated to couple the pressurizedgas at source pipe 76 into the sample chamber 64, through the B valve soas to compress the gas bubbles in the sample trapped there to a smallvolume. The second valve B is then operated to trap the compressedsample between the first and second valving plates 50 and 51 in valves Aand B respectively. This trapped volume may be a known volume or anunknown volume of high reproducibility depending on the application. Thesample pump 70 is then operated in the direction so as to empty the restof the sample 56 not so trapped through the lines 74 and 66. Thisempties these lines and the reservoir 54 and prepares the system to becleaned out with solvent. The solvent is then pumped in through the samelines to fill the reservoir 54 and rinse excess sample away. The solventis then pumped to waste. Alternatively, the pump 70 may substitute forthe compressed gas at source pipe 76. The valves and pump are thenoperated so as to free the trapped sample in sample chamber 64 and topump a known quantity of solvent through the lines and to push thetrapped sample into the sample chamber in preparation for the nextdesired sample preparation step.

Referring again to FIG. 1, the rest of the sample preparation systemwill be described. A key element in the system is the liquid pump 84.This pump is reversible such that it may pump liquid in either directionthrough the pipes 86 and 88 which are coupled to the pump's input andoutput ports. The pump 84 must be capable of delivering repeatedly, veryaccurate volumes of liquid since it will be used to pump in precisevolumes of diluent to dilute the known volume of sample released fromthe sample metering valve. Typically pumps with inlet and outlet checkvalve structures are not reproducible enough in the deliveries of knownvolumes because of the dead volume of liquid which inevitably resultsfrom the check valve operation. Any type of pump with an unpredictableor not reproducible dead volume associated with its output valvestructure will not be satisfactory. Dead volume is the unknown, variablevolume of liquid trapped by the output valve mechanism which will bereleased the next time the valve opens to thereby destroy the accuracyof the volume delivered by the pump. Any type of pump and valve/flowmeter combination which can accurately deliver a user defined volume ofdiluent will be satisfactory. A positive displacement pump which isaccurate to within 1% volumetric accuracy and 1% relative standarddeviation in dispensement precision will be adequate. One type of pumpwhich works well is a "swash" pump. This type, as is known by thoseskilled in the art, uses a tilted rotating shaft inside a cylinder. Thewalls of the cylinder have input and output ports located on oppositesides at different levels such that the rotation of the shaft opens andcloses the ports sequentially. The axial displacement of the shaftwithin the cylinder causes liquid to be drawn in from one port andpumped out the other port. The direction of pumping may be changed byreversing the direction of rotation of the pumping plate. The rotationof the plate is controlled by a stepper motor or other mechanism whichcan precisely control the position of the plate to maintain the outputport closed when pumping is not occurring. Such pumps are a manufacturedby Fluid Metering Inc. and are patented in U.S. Pat. Nos. 3,168,872 and3,257,953 both of which are hereby incorporated by reference. Othertypes of pumps such as syringe pumps will also suffice to practice theinvention, but in high volume applications, these syringe pumps may notbe commercially practicable.

Another important criteria regarding the selection of the pump is thatthe sealing mechanism be reliable for a large number of cycles withoutfailure.

The pump 84 is coupled by a control bus 85 to a control circuit/userinterface 98 which provides control signals to cause the pump 84 to pumpan amount of liquid defined by the control signal in the directiondefined by the control signal. The pump drive mechanism may be any typeof mechanism such as pneumatic, or stepper motor which can provide thenecessary precision of rotor position and accuracy in delivery volume.The details of the control circuit/user interface are not critical tothe invention, and those skilled in the art will appreciate that manydifferent type of control mechanisms may be used to control the pumpsand valves in the system to do a plurality of different functions and toprepare a plurality of different types of samples for analysis. Forexample, a programmed digital computer driving stepper motor interfacecircuits and interface circuits for solenoid operated valves may beused. Further, the control circuit may be dedicated logic, a statemachine or a mehanical or analog electronic computer. The interface tothe pump and valves may also be via electrically driven pneumatic orhydraulic valves which send pneumatic or hydraulic signals to the pumpand valves in the system to cause them to perform the desired functionsin the proper sequence. Further, the control circuit 98 may not be acircuit at all in some embodiments, but instead may be a human operatorwho does all the calculations and operates the valves in accordance withthe sequence of steps necessary to process a particular type of sample.

The pipes 86 and 88 are coupled, respectively, through valves 90 and 92to manifolds 94 and 96. All valves, like the pump 84, are coupled bycontrol signals to a control circuit/user interface 98. The controlsignals are not shown in full detail since to do so would undulycomplicate the drawing. All valves may be solenoid operated valves, orthey may be pneumatically operated or driven by stepper motors. Themanner of driving the valves is not critical to the invention.Regardless of the type of drive mechanism, all valves should be suchthat they may be opened and closed upon receipt of the proper controlsignal from whatever control mechanism is being used to control thesystem. For example, these control signals arrive on control buses 100and 102 for valves 90 and 92, respectively.

The manifolds 94 and 96 are coupled through a plurality of valves to avariety of sources of inputs and to a variety of destinations ordevices. For example, valve 103 couples a pressure source 104 to themanifold 94. The other valves and facilities in the system are: valve106 which couples the vacuum source 108 to the manifold 94; valve 110which couples water supply 112 to the manifold 94; valve 114 whichcouples the manifold 94 to a 6 way injection valve and to the fill pipe26; valve 118 which couples the manifold 94 to the nozzle 28; valve 120which couples manifold 94 to an isolation chamber (not shown) in theprocess stream sample valve 122; valve 124 which couples the manifold 96to a filter 126 and an analyzer 128; valve 130 which couples manifold 96to an input port 132 for a first solvent; valve 134 which couples themanifold 96 to an input port 136 for a second type of solvent; valve 138which couples the manifold 96 to an input port 140 for a third type ofsolvent; valve 142 which couples the manifold 96 to an effluent pipe 144which is coupled to the fill/empty pipe 20 through a three way valve146. The three way valve 146 has an input port 148 which is coupledthrough a filter 150 to the isolation chamber of the process streamsample valve 122. The three way valve 146 also has two output ports oneof which is the fill/empty pipe 20 and the other of which is theeffluent line 144. A control signal on the control bus 150 controlswhich of the output ports of the valve 146 at any particular time iscoupled to the input port 148. Each of the valves coupled to themanifolds 94 and 96 is capable of being controlled by the controlcircuit/user interface circuit 98 such that a control signal from theuser interface may open or close each valve.

THE PROCESSES FOR SAMPLE PREPARATION Solid and Very Viscous SamplesWhich Cannot be Pumped

The system described above is capable of preparing in different waysmany different types of samples from several different sources foranalysis by the analyzer 128. For example, the system provides thefacility to convert solid samples to diluted liquids at a knownconcentration. This process involves the following steps. For tablet orgranular samples or viscous liquids which do not readily flow, the cup12 is removed from the cap 14 and taken to the location of the sample. Auser determined quantity of the sample is placed in the cup. This may bedone by using the weighing machine 18 to weigh the cup before and afterplacing the sample therein to determine the mass of the sample which hasbeen placed in the cup. The weighing machine 18 can be used to transmitthe weight data directly to the control circuit 98 via the bus 152. Thecontrol circuit 98 may then use this information to perform calculationsto adjust the dilution factors appropriately, or simply retransmit suchinformation to another device.

The cup is then placed back on the cap 14. If the sample is a tablet,the control circuit 98 turns on the mixer/grinder 30A to grind thetablet into smaller pieces to speed up the process of dissolving it indiluent. For granulated or viscous samples, this step may be eliminated.

Next, the sample must be dissolved to form a solution of the properviscosity, composition, and concentration for pumping through the LCcolumn 128 or other analyzer. Because the control apparatus 98 knows theweight of the sample in the cup from previous steps and has the desiredconcentration from the user, a calculation may be performed by thecontrol apparatus or by the human operator (hereafter an automatedcontrol apparatus will be assumed, although the processes may beperformed manually under the control of a human operator who eitherphysically controls the valves and switches driving force to the pumpfor times calculated by the operator) to determine how much solvent ordiluent to pump into the cup 12 to get the desired concentration. Thecontrol/user interface system 98 (hereafter the control system) thensends the proper control signals to switch the proper valves to theproper states to pump the selected solvent or solvents into the cup andsends the proper control signals to turn on the pump 84 and cause it topump in the proper direction to deliver the calculated amount of solventinto the cup 12. For example, if solvent number 1 is to be used, controlsignals would be generated to open valve 130 and to open either valve118 or valve 114 depending upon whether the walls were to washed down ornot. The proper control signals to activate the pump 84 would then begenerated to cause the pump to pump solvent from the port 132, throughthe manifold 96 and the pipe 88 through the pump 84 and the pipe 86,through the manifold 94 and out into the cup 12 through either thenozzle 28 or the fill pipe 26. These control signals to the pump aresuch as to cause the necessary volume of solvent to achieve the desiredconcentration to be pumped into the cup 12.

After the solvent is pumped in, the mixer/grinder 30A may be turned onto mix the solvent and the powder or solder chunks to dissolve thesolids. Of course with granulated or powder samples the above noted stepof turning on the mixer/grinder 30A before pumping in the solvent may beeliminated. In such embodiments, the solvent may be pumped in as soon asthe cup is attached to the lid, and then the mixer/grinder 30A may beturned on to dissolve the sample.

Once the sample is dissolved, if the proper concentration of solvent ispresent and the solution is homogeneous, the control system forces apredetermined volume of the diluted sample to be pumped to the LCsystem. To do this the control system 98 causes valves 124, 103 and 114to be opened and valve 145 in the effluent line to be closed. The valve146 is caused to couple the portion 160 of the effluent line to theportion 144 of same and pipe 148 is closed off by the valve 146. Theresult of all these valve operations is that pressurized gas from thepressure source 104 pressurizes the sample preparation chamber definedby the cup 12 and the cap 14 via the manifold 94 and the fill pipe 26.The seals 16 prevent the pressurized gas from leaking away. The pressureforces the liquified sample in the chamber to enter the portion 160 ofthe effluent line and pass through the valve 146 to the portion 144 ofthe effluent line. Because the valve 145 is closed, the sample entersthe pipe 162 and passes through the manifold 96 where it passes throughthe valve 124, pipe 164 and filter 126 and if forced through the liquidchromatography analyzer 128.

The problem with this approach is that it is not known how much liquidhas been pumped. Generally, it is desirable to pump between 4 to 6 timesthe volume of the connecting tubings (as a minimum) through the systemto flush out the lines and to fill the "loop" in the valve in the LCsystem 128. It is preferred because of timing considerations to knowexactly when the sample loop is filled up so that the timing ofexamination of the output may be established.

If the proper concentration for the sample was not present after thesolvent was pumped in, the sample metering valve may be operated asdescribed above by the control system to take a known volume of sampleand isolate it. Then the control system causes the three way valve 146to couple pipe 160 to pipe 144 and valve 145 to open. Then, the valves102 and 114 are opened, and the remaining sample is flushed through theeffluent line 160 to waste by the pressurized gas. Next, if desired, thewalls may be washed down by opening one of valves 130, 134 or 138 andthe valves 92, 90 and 118 and activating the pump to pump some userdefined or fixed quantity of a solvent or solvents through the nozzle 28to wash down the walls. The mixer/grinder 30A which may a variable speedmotor 30 in the preferred embodiment, may be turned on at a high speedduring or after the sprinkling process to create turbulence to morethoroughly clean the walls. After the excess sample and solvent arecleaned off the walls, the waste solvent and sample is the cup 12 may bedriven to waste by use of the pressurized gas source 104 as definedabove. Thereafter, the control system operates the sample metering valveto release the isolated sample back into the cup 12, and operated thepump 84 to pump a calculated amount of solvent into the cup to achievethe user defined concentration for the diluted sample. The manner ofdoing these operations is as defined above.

Once the desired sample concentration is reached, and the liquid in thecup is homogeneous, the system is ready to have the diluted samplepumped through the LC system. To do this, the pressurized gas methoddefined above can be used, but the preferred embodiment of getting theliquid sample out of the sample chamber, regardless of whether it wasoriginally two phase liquid/solid, two phase liquid/liquid, solid orextremely viscous is to pump the diluted sample out using the pump 84.The reason this pumped method is preferred is that the system is lesscomplicated from a timing standpoint. With a known volume system, it isknown how many pump strokes are necessary to move liquid from the samplecup 12 to the LC system 128. Thus the time to get the sample to the LCsystem is known, and the control system can control the LC system basedupon this known time. If the pressurized gas method is used, the time ittakes the liquid sample to get from the sample cup to the LC system isnot known because of the unknowns of the viscosity of the diluted samplechanging from one sample to the next, and any tubing or fitting changesmay also alter the timing. To control such a system, there would have tobe an interrupt generated to the control processor or control systemwhen the LC system 128 received the required amount of sample and isready to go. A polled system would also work. These timingconsiderations, although not terribly complicated, are additionalfunctions the control system must perform.

To pump the sample to the LC system 128 using the pump 84, the valves114, 90, 92 and 124 are opened, and the pump is energized to pump from 4to 6 times the tubing volume, typically 10 to 30 millimeters of dilutedsample, to the fill pipe 26, manifold 94, pipe 86, pipe 88 and manifold96 and pipe 164 as the pathway. This provides better control of thevolume of sample delivery to the LC system so that the control of the LCanalysis system 128 needs no interrupt or polling to indicate when thesample has arrived. To perform the above steps however requires that theamount of solvent/diluent pumped into the sample preparation chamber besuch as to bring the liquid level of the diluted sample at the finalconcentration to a level above the end of the fill pipe 26. To avoidsuch complications, it is preferred to put the end 166 of the fill pipe26 close to the bottom 168 of the sample preparation chamber. Thiseliminates the need for tradeoffs regarding the volume of the isolationchamber and the volumes of solvent/diluent to pump in to make sure thatat all volumes of samples, the final liquid level after dilution will beabove the level of the end 166 of the fill pipe 26. In the preferredembodiment, the level of the end 166 of the fill pipe 26 may be manuallyor automatically adjusted to account for such variations. This providesthe extra facility of being able to keep the end 166 of the fill pipeoff the bottom for samples which have sediment or solid material thereinwhich could plug the fill pipe 26 if they were sucked up into the fillpipe.

Sample Dilution Without the Use of a Sample Metering Valve

The sample preparation process where clean, homogeneous samples are tobe analyzed, there is no need for the step of homogenization. In such asituation, a 6 way valve may be used to introduce the sample to the cup12. This valve may be used to isolate a known volume of sample in a loopbetween valve ports 182 and 184. FIGS. 10 and 11 illustrate how this canbe done using two states of a 6 way valve. In FIG. 10 the 6 way valve isshown in the state in which the sample may be drawn from the sample vat.In this state, port 180 is connected to the sample vat and is alsoconnected to port 182. Port 182 is always coupled to port 184 by aninternal or external passageway regardless of the state of the valve. Itis this passageway which will be used as the isolation chamber in placeof the sample isolation chamber in the sample metering valve. The port186 is coupled to the port 184 in this first state, and is also coupledto the manifold 94 through the valve 114. While the 6 way valve is inthe state shown in FIG. 10, the control system 98 opens the valves 114,90, 92, 142 and 145 and operates the pump to apply suction to the port186. This draws sample up from the sample vat and fills the loop betweenports 182 and 184 with sample. The pumping need only be long enough thatthe entire passageway between ports 182 and 184 is filled.Alternatively, the sample loop between ports 182 and 184 while the valveis in the state indicated by FIG. 10 may be filled manually by attachinga syringe filled with sample, or any device capable of forcing flowthrough the sample loop, to port 180 and forcing sample into the sampleloop. Port 186 could then be simply connected to any waste receptacle.

The control system then switches the 6 way valve to the state shown inFIG. 11. In this state, the ports 182 and 184 are coupled, respectively,to ports 188 and 190. The port 190 is coupled to the manifold 94 by anadditional solenoid or pneumatically operated valve 192, and the port188 is coupled to the cup 12 via the fill pipe 26. When the 6 way valveis operated by the control system to put it in the state shown in FIG.11, the sample that filled the passageway between the ports 182 and 184is isolated. The control system then opens the valves 192, 90, 92 andone of the solvent valves 130 or 134 or 138 and operates the pump 84 topump a known volume of solvent into the cup 12. The known volume ofsolvent is computed based upon the known volume of the passagewaybetween the ports 182 and 184. The isolated sample and the known volumeof solvent are then mixed by turning on the mixer/grinder 30.Thereafter, the diluted sample may be transferred to the analyzer 128 inany of the manners described above. In alternative embodiments, theports 180 and 186 may be connected to a sample line with its own pump tofill up the passageway between the ports 182 and 184. The ports 188 and190 in these embodiments are coupled, respectively, to the fill pipe 26and to the manifold 94, and the valve 192 is not needed.

PREPARING SAMPLES TAKEN FROM A PROCESS STREAM

The system according to the teachings of the invention is capable ofisolating known volumes of samples from a process stream and preparingsame for the analyzer. The valve 122 in FIG. 1 is used for this purpose.Control system 98 implements the process by causing the valve 122 toextract and isolate a known volume of sample flowing in process stream192. The valve 122 is preferably an ISOLOK™ valve series M$ manufacturedby Bristol Engineering of Yorkville, Illinois or equivalent. This valveis similar in operation to the valve shown in FIGS. 2 and 3 except thatthe there are additional ports 194 and 196. These ports are placed onthe cylinder of the ISOLOK valve such that when the piston of the valveis in the retracted position, the isolation chamber of the ISOLOK valveanalogous to the chamber 21 in FIGS. 2 and 3 is in a position such thatpressurized gas or liquid in the pipe 194 will sweep the isolationchamber clear of sample and drive it into pipe 196 or vice versa.

To sample a process stream then, the valve 122 is operated by thecontrol system 98 to isolate an aliquot of sample from the processstream 192. Then, the valves 92, 90, 120 and one of the solvent valvesare opened. In addition, the valve 145 is closed, and the three wayvalve 146 is operated to couple the pipe 148 to the pipe 160. The pump84 is then operated to draw a calculated amount of solvent from thesolvent source and drive it through the pipe 194, the ISOLOK valve 122and the pipe 196 to sweep the isolated sample out of the isolationchamber and into the cup 12 through the valve 146 and the effluent line160. The amount of solvent drawn by the pump 84 is calculated from thedesired final concentration and the known volume from the ISOLOK valve.Although the exact volume from the ISOLOK valve will not be known to thesame precision as would the volume in the isolation chamber of thesample metering valve because of unknown dead volumes in the sealingrings, the precision is good enough for most applications.

Next, the mixer/grinder 30 is activated to homogenize the sample, andthe liquid is then driven to the analyzer 128 for analysis in the mannerdescribed above.

Processing Slurry Samples

Slurry and other types of samples sometimes have gas bubbles entrainedin the liquids. Gas bubbles may be at least partially drawn off beforesample aliquot isolation in the system of FIG. 1 by the application ofvacuum to the sample preparation chamber before operating the samplemetering valve. The lower than atmospheric pressure causes outgassing ofthe gas entrained in the slurry or in foam bubbles on top of the liquid.Application of the vacuum is performed by the control system 98 byopening the valves 102 and 114 after the slurry is placed in the cup 12in any of the processes described above. After the gases are drawncompletely or substantially off, the sample metering valve 36 isoperated to draw in an aliquot of slurry and to compress it as describedabove. After compression, a known volume of the compressed slurry isisolated, and the remaining slurry is transferred to waste as describedabove. The walls of the sample preparation chamber may also be washeddown as described above if desired. Finally, the sample metering valve36 is operated to release the isolated sample aliquot, and a knownvolume of solvent is pumped in as described earlier to arrive at thefinal concentration (serial dilution is possible in this process as itis in any of the processes described herein). The mixer/grinder 30 isthen turned on by the control system 98, and the required amount of thediluted sample is transferred to the analyzer 128 as described above.

The water supply 112 may be used to flush out all the pipes in thesystem by properly operating the valves, but its principal use is influshing out the sample preparation chamber.

Referring to FIG. 12 there is shown a diagram of another embodiment ofthe sample preparation system of the invention. In this embodiment, thesample valve is comprised of the three way valves V1, V2 and V3 whichoperate in the manner described with respect to FIG. 9. Further, themanifolds 94 and 96 are replaced by rotary valves 1 and 2. All thevalves are controlled by a control system (not shown) which causes thevalves to operated in the proper sequence as described below. To take asample in the system of FIG. 12, the cup 12 is filled with sample, andvalves V1, V2 and V3 are operated to gate the drain line 200 to wasteline 202 through the sample loop and the dead volume. The sample isdriven to waste by pressurizing the cup via proper operation of V7 topressurize the gas reservoir 204 with gas and then to use the gasreservoir pressure to pressurize the cup through the valves V7, V6 andthe pressure regulator 206.

After the sample loop has been filled, valves V1 and V2 are operated toisolate the sample loop, and V7, V4 and rotary valve 1 are operated topressurize lines 206, 208, 210, 212 and 200 to drive remaining sampleback into the cup. Then the remaining sample in the cup is driven towaste by changing valve V3 to direct flow through drain line 200 to thewaste line 202 and the cup is again pressurized using the gas reservoir204, valves V7 and V6, pressure regulator 206 and the lines 214 and 216.This forces all the sample out of the cup.

The cup is then rinsed by operating rotary valves 1 and 2 and valves V4and V5 and pump 220 to pump solvent from reservoir 222 into the sprayerreservoir 224. The sprayer reservoir is then pressurized by operatingvalves V7, V4, and V5 and rotary valve 1 so that pressurized gas isdirected from gas reservoir 204 into the sprayer reservoir. The cup isthen washed by operating valve V5 so as to direct the solvent in thesprayer reservoir 224 through the rotary sprayers 226 via line 228. Therotary sprayer directs the pressurized solvent stream around inside thecup to wash down all the internal structures by solvent impact. The cupis then emptied of solvent by pressurizing the cup in the mannerdescribed above and operating valves V1, V2 and V3 so that the solventis directed through pipe 230 and the dead volume out through the wastepipe 202.

The fixed volume of sample trapped in the sample loop is then drivenback into the cup by operating the pump 220 and rotary valves 1 and 2 tosuck a desired diluent/solvent from a reservoir 222 (or other solventsin other reservoirs coupled to rotary valve 2 could be used) and pump itthrough pipe 232, valve V4, pipes 208 and 210 and 212, the dead volume,the sample loop and the drain pipe 200. The pump 220 is driven to pump aknown volume of the selected solvent into the cup thereby pushing theknown volume of sample in front of the pumped solvent into the cup alongwith a known amount of solvent. Pulse dampeners 240 and 242 remove anypulses from all pumping actions done by the system to minimize oreliminate any cavitation and bubbles from the system. As was the casewhen the sample was first introduced into the cup, a homogenizer orultrasonic mixer or any other type of stirrer (not shown) may be used tomix the sample, homogenize it or mix it thoroughly.

Having reduced the sample aliquot to the proper concentration, thesystem is now ready to be pumped through the chromatography system. Thisis done by operating valves V1, V2, V3 and V4 and rotary valves 1 and 2such that a path is established from the drain pipe 200 through the pump220 and out pipe 244 to the chromatography system for assay. If it isdesired to sample from a higher layer, the pipe 246 may be used byproperly operating the valves in the system to use pipe 246 as the inputpath to the pump 220. The pipe in the system which still have sample inthem and the cup may be purged with solvent in a manner which will beapparent to those skilled in the art from the above discussion.

Another manner of using the system of FIGS. 12 is to put a liquid samplecontaining a chemical of interest in solution in the cup. The pump andvalves may then be operated to pump a known volume of the sample throughthe liquid chromatography column to concentrate the chemical of intereston the active agent which coats the packing material of the column.

Although the invention has been described in terms of the preferred andalternative embodiments detailed herein, other alternative embodimentsmay be apparent to those skilled in the art. All such alternativeembodiments which appropriate the spirit of the invention are intendedto be included within the scope of the claims appended hereto.

What is claimed is:
 1. A process for preparing a solid sample forchemical assay by an assay system comprising the steps of:(a) placing aknown amount of a solid sample into a sample preparation chamber havinga grinding and stirring mechanism therein and using a programmableelectronic control system which possesses data regarding the quantity ofsaid known amount of sample which has been placed into said samplepreparation chamber to perform steps (b) through (m) automatically; (b)grinding the known amount of sample in the sample preparation chamberuntil it is in pieces small enough to be efficiently dissolved in asolvent; (c) placing a known quantity of a solvent in the samplepreparation chamber; (d) mixing said known amount of a sample with saidknown quantity of solvent in the sample preparation chamber, therebycreating a homogeneous mixture; (e) withdrawing a known volume of saidhomogenized mixture from the sample preparation chamber into a samplemetering valve; (f) pressurizing said withdrawn volume of saidhomogenized mixture in said sample metering valve to compress any gasbubbles in said withdrawn volume of said homogenized sample, therebygenerating a pressurized, homogenized mixture; (g) isolating a knownvolume of said pressurized, homogenized mixture in said sample meteringvalve to obtain a non-isolated volume of said homogenized mixture in thesample preparation chamber and an isolated known volume of saidpressurized, homogenized mixture which is isolated from the samplepreparation chamber; (h) flushing said non-isolated volume ofhomogenized mixture from the sample preparation chamber to waste; (i)releasing the isolated known volume of said pressurized homogenizedmixture back into the sample preparation chamber; (j) if a predeterminedsample concentration has been reached, continuing on to step (k), but ifthe predetermined sample concentration has not been reached, repeatingsteps (c)-(i) until the predetermined sample concentration has beenreached and then continuing on to step (k); (k) pumping a predeterminedvolume of the released, homogenized mixture to said assay device (l)flushing any released, homogenized mixture remaining in the samplepreparation chamber to waste; and (m) washing down said samplepreparation chamber with a solvent and flushing the solvent to waste tothereby prepare said sample preparation chamber to process anothersample.